From Biomarker to Companion Diagnostic: of Analytical and Clinical Validation, Regulatory Affairs, and Intellectual Property

In the August 24^th early online issue of Drug Discovery Today (reference), Michael Nohaile from Novartis Pharma AG discusses the key factors required to translate a promising biomarkers into an effective companion diagnostic (CDx).  Based on a pragmatic staging scheme of drug – CDx co-development (figure 1), the author dissects the complex cross-functional interactions between of analytical and clinical validation, regulatory affairs, and intellectual property management.

Fig.1

On the analytical validation front, the author stresses the importance of timely assay platform selection, the need for proper consideration of pre-analytical parameters (see my earlier post: Biomarker Research: The Pre-analytical Puzzle), and the critical issue of the synchronization of the assay validation process to meet clinical development milestones.  Failure to complete assay validation before the initiation of pivotal clinical will require the conduct of complex and expensive bridging studies to satisfy the regulatory requirement for CDx.

On the clinical validation front, the author discusses the issue of adequate sample ascertainment rate from clinical studies in the context of prospective-retrospective (predefined analysis of samples from a completed study) CDx clinical validation strategies, and the issue of the statistical power for purely prospective CDx clinical validation studies.  In particular, serious consideration should be given to the decision of including or excluding marker negative patients in such studies.  On the one hand, inclusion of marker-negative patients is required to determine the positive and negative predictive value of the candidate CDx.  On the other hand, beyond being less expensive and potentially faster, studies that exclude marker-negative patients may also present an ethical advantage in cases where the potential treatment benefit is expected to be negligible in marker-negative individuals.

From a regulatory affairs perspective, the fact that CDx are regulated by the Center for Devices and Radiological Health (CDRH) implies that specific regulatory expertise is required for the successful prosecution of CDx (see also my earlier post about recent FDA guidance: Companion In Vitro Diagnostics (IVD) Development: some clarity at last).  In particular, the fact that the risk / benefit analysis for CDx is entirely tied to the risk / benefit profile of the associated drug implies a close collaboration between the drug reviewing authorities (CDER/ CBER) and the device reviewing authorities (CDRH).

Finally, from an intellectual property, the author discusses the issue of the timing of patent filing and the more global issue of patentability of biomarkers.

Thierry Sornasse for Integrated Biomarker Strategy